The scientists arrived at the new findings by comparing gene activity levels in different regions of the brain. They identified adult brain regions where genes linked to the construction of new connections between cells have higher activity levels. The same genes are also highly active in young brains, so the researchers called this pattern of gene activity childlike.

"We already knew that the adult human brain generally has more activity among these genes when compared with other closely related species, including chimpanzees and monkeys," said first author Manu S. Goyal, MD, a fellow in neuroradiology at Washington University. "Our new results connect this activity to a form of energy production known to be helpful for building biological structures, such as the new nerve cell branches needed to add connections in the brain."

Scientists believe that new links between brain cells help encode new memories and skills long after the brain stops growing.

Several years ago, senior author Marcus Raichle, MD, professor of radiology, psychology, neurology, neurobiology and biomedical engineering, was investigating the brain's voracious consumption of sugar and oxygen to make energy and enable other functions when he noticed that a few areas of the brain consumed sugar at exceptionally high rates. He and his colleagues later showed that this was because these regions were actively engaged in an alternative energy-making process called aerobic glycolysis.

"Aerobic glycolysis happens to be the form of sugar consumption favored by cancer cells and other rapidly growing cells," said Goyal. "This made us wonder if the brain regions that use aerobic glycolysis were also those that had the most childlike gene activity, namely those that help form new brain cell connections."

For the new study, Raichle collaborated with Michael Hawrylycz, PhD, a scientist at the Allen Institute for Brain Science. The institute's accomplishments include creating the Allen Human Brain Atlas, a database detailing the activity of genes in different parts of the brain and from people of different ages.

When researchers used the atlas to look at gene activity in brain regions with high rates of aerobic glycolysis, they found that these regions had more childlike gene activity than other brain regions. They also identified more than 100 genes that consistently were more active in these regions than in others.

As part of the study, Goyal also analyzed data from earlier research by other scientists to show that there is more aerobic glycolysis throughout the brain in young children.

Aerobic glycolysis is less efficient for energy production than oxidative glycolysis, the alternative method that uses oxygen and sugar. But scientists think the former is a better source of energy for rapid growth.

"Even in adults, there are parts of the brain that still are rapidly changing and adapting, and that's likely why aerobic glycolysis continues to be used in the adult brain," Goyal said.

The researchers now are studying whether problems in specific brain cells that use aerobic glycolysis contribute to neurodevelopmental problems such as autism or mental retardation or to neurodegenerative disorders like Alzheimer's disease.

"The ability to support the metabolic requirements of adult brain cells to create new connections may one day be important for treating brain injuries and neurodegenerative disorders," Goyal explained. "We have a lot of work to do, but this is an intriguing insight."

THE ALLEN INSTITUTE WEIGHS IN

"These experiments and analysis represent the first union of its kind between functional imaging data and a biological mechanism, with the Allen Brain Atlas resources helping to bridge that gap," comments Michael Hawrylycz, Ph.D., Investigator with the Allen Institute for Brain Science and co-author of the study. Data from PET scans provides structural insight into the brain, but until now, has not been able to elucidate function. "Now we can make the comparison between the functional data and the gene expression data," says Hawrylycz, "so instead of just the 'where,' we now also have the 'what' and 'how.'"

The brain needs to constantly metabolize fuel in order to keep running, most often in the form of glycolysis: the breaking down of stored sugar into useable energy. PET scans of the brain, which illuminate regions consuming sugar, show that some select areas of the brain seemed to exhibit fuel consumption above and beyond what was needed for basic functioning. In cancer biology, this same well-known phenomenon of consuming extra fuel—called "aerobic glycolysis"—is thought to provide support pathways for cell proliferation. In the brain, aerobic glycolysis is dramatically increased during childhood and accounts for as much as one third of total brain glucose consumption at its peak around 5 years of age, which is also the peak of synapse development.

Since aerobic glycolysis varies by region of the brain, Hawrylycz and co-author Marcus Raichle, Ph.D., at Washington University in St. Louis, wondered whether regions of the brain with higher levels of aerobic glycolysis might be associated with equivalent growth processes, like synapse formation. If so, this would point to aerobic glycolysis as a reflection of "neoteny," or persistent brain development like the kind that takes place during early childhood.

In order to delve into the significance of aerobic glycolysis, researchers examined the genes expressed at high levels in those regions where aerobic glycolysis was taking place. The team identified 16 regions of the brain with elevated levels of aerobic glycolysis and ranked their neotenous characteristics. True to prediction, they found that gene expression data from those 16 regions suggested highly neotenous behavior.

The next phase was to identify which genes were specifically correlated with aerobic glycolysis in those regions. The Allen Brain Atlas resources proved crucial in this task, helping to pinpoint gene expression in different regions at various points in development. The Allen Human Brain Atlas was used to investigate the adult human brain, while the BrainSpan Atlas of the Developing Human Brain, developed by a consortium of partners and funded by the National Institutes of Health, provided a window into how gene expression changes as the brain ages.

Analysis of the roles of those genes pointed clearly towards their roles in growth and development; top genes included those responsible for axon guidance, potassium ion channel development, synaptic transmission and plasticity, and many more. The consistent theme was development, pointing to aerobic glycolysis as a hallmark for neotenous, continually developing regions of the brain.

"Using both the adult and developmental data, we were able to study gene expression at each point in time," describes Hawrylycz. "From there, we were able to see the roles of those genes that were highly expressed in regions with aerobic glycolysis. As it turns out, those genes are consistently involved in the remodeling and maturation process, synaptic growth and neurogenesis—all factors in neoteny." "The regions we identified as being neotenous are areas of the cortex particularly associated with development of intelligence and learning," explains Hawrylycz. "Our results suggest that aerobic glycolysis, or extra fuel consumption, is a marker for regions of the brain that continue to grow and develop in similar ways to the early human brain."